Cyclooxygenase-2 Induced Pancreatic Cancer

环氧合酶 2 诱发胰腺癌

• 批准号: 8212143
• 负责人: SUSAN M FISCHER
• 金额: $ 31万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8212143
• 关键词: Adenocarcinoma; Adenylate Cyclase; Age-Months; Animal Disease Models; Animal Model; Automobile Driving; Binding; CREB1 gene; Calcium; Cells; Characteristics; Chemoprevention; Chronic; Coxibs; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cyclin D1; Data; Development; Dinoprostone; Disease; Dominant-Negative Mutation; Epidermal Growth Factor Receptor; Etiology; Future; GTP-Binding Proteins; Genes; Health; Human; In Vitro; Incidence; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Inositol; Investigation; Lesion; Leukocytes; Link; Lymphocyte; MAP Kinase Gene; Malignant Neoplasms; Malignant neoplasm of pancreas; Measures; Mediating; Metaplasia; Metaplastic; Molecular; Mus; Neoplastic Processes; PTGS2 gene; Pancreas; Pancreatic Adenocarcinoma; Pancreatitis; Pathway interactions; Phenotype; Phosphorylation; Play; Prevention; Prostaglandins; Protein Kinase C; Receptor Activation; Recruitment Activity; Research; Role; SRC gene; Signal Pathway; Signal Transduction; Signaling Molecule; Skin; Small Interfering RNA; Therapeutic; Tissues; Transgenic Mice; Up-Regulation; Vascular Endothelial Growth Factors; Work; celecoxib; chronic pancreatitis; cyclooxygenase 2; cytokine; human WFDC2 protein; human disease; inhibitor/antagonist; keratin 5; macrophage; neoplastic; pancreatic neoplasm; prevent; promoter; receptor; response; transcription factor; tumor; tumorigenic

DESCRIPTION (provided by applicant): Investigations into the role of cyclooxygenase-2 (COX-2) in pancreatitis and pancreatic cancer have been very limited. A recently generated transgenic mouse that over- expresses COX-2 under the control of a keratin 5 promoter, K5.COX-2, develops spontaneous pancreatitis leading to pancreatic adenocarcinoma that has many of the same histological and molecular characteristics as the human disease. This occurs with a 100% incidence and is fatal by 8 months of age. The major prostaglandin (PG) product, PGE2, binds to one or more of the 4 EP receptors. EP2 and EP4 are linked to adenylate cyclase causing an increase in cAMP and subsequent activation of protein kinase A (PKA) and phosphorylation of CREB. Preliminary data indicate that the cAMP/PKA/pCREB pathway is highly activated in pre-lesion pancreata of K5.COX-2 mice, however, the MAPK/Akt/NFkB pathway is also highly activated. We hypothesize that activation of both the cAMP/PKA/pCREB and MAPK/Akt/NFkB signaling pathways are required for a full neoplastic response as is the inflammatory response, and that inflammation is driving the metaplastic and neoplastic changes. Aim 1 will determine the requirement for PG signaling through the cAMP/PKA/pCREB pathway for adenocarcinoma development by generating transgenic mice with inducible, targeted activated CREB on a wildtype background, and dominant negative (dn)CREB on the K5.COX-2 background. Aim 2 will determine the critical involvement of MAPK/Akt/NFkB signaling in adenocarcinoma development through the use dnAkt/K5.COX-2 bitransgenic mice and the use of MAPK and NFkB inhibitors. Activation of c-Src, EGF receptors, Erk, Akt and NFkB will be assessed in wild type, pre-lesion and lesions from K5.COX-2 pancreata. Aim 3 will determine whether prostaglandins are driving acinar metaplasia by elevating cytokines that then recruit leukocytes. The effect of inhibition of COX-2 with celecoxib, or of inhibiting cytokine synthesis with pentoxyfylline, on cytokine expression, inflammatory cell infiltration and the development of acinar metaplasia and pancreatic cancer will be assessed. The effect of inhibition of COX-2 or cytokine synthesis on inflammatory cell infiltration in established lesions will also be determined to assess whether this will prevent further progression or reversion of the disease. PUBLIC HEALTH RELEVANCE: The proposed studies are significant because pancreatic cancer is one of the most fatal of all human malignancies and the lack of good animal models has severely hampered research into its etiology, prevention and treatment. Because of the associations between chronic inflammation, COX-2 and human pancreatic cancer, it is likely that the proposed work will generate information on the signaling pathways and receptors that are critical determinants in pancreatic cancer development, which should be useful for guiding future studies on chemoprevention and therapy.

描述（由申请人提供）：对环氧合酶-2（COX-2）在胰腺炎和胰腺癌中的作用的研究非常有限。最近生成的转基因小鼠在角质5启动子K5.cox-2的控制下过度表达COX-2，会产生自发性胰腺炎，导致胰腺腺癌具有与人类疾病相同的组织学和分子特征。这发生在100％的发病率，到8个月大。主要前列腺素（PG）产品PGE2与4个EP受体中的一个或多个结合。 EP2和EP4与腺苷酸环化酶有关，导致cAMP增加，随后激活蛋白激酶A（PKA）和CREB的磷酸化。初步数据表明，CAMP/PKA/PCREB途径在K5.cox-2小鼠的肿瘤前胰腺中被高度激活，但是，MAPK/AKT/NFKB途径也被高度激活。我们假设CAMP/PKA/PCREB和MAPK/AKT/NFKB信号通路的激活是完全的肿瘤反应，炎症反应也需要，并且炎症正在推动转移和肿瘤变化。 AIM 1将通过CAMP/PKA/PCREB途径来确定PG信号传导的需求，以通过在野外型背景上产生具有诱导，靶向活化的CREB的转基因小鼠，并在K5.COX-CRECKDEND上具有诱导的，有针对性的激活CREB。 AIM 2将通过使用DNAKT/K5.COX-2 BITRANSGENIC小鼠以及MAPK和NFKB抑制剂的使用，确定MAPK/AKT/NFKB信号传导在腺癌发育中的关键参与。 C-SRC，EGF受体，ERK，AKT和NFKB的激活将以K5.COX-2胰腺的野生型，质量和病变进行评估。 AIM 3将确定前列腺素是否通过升高然后募集白细胞的细胞因子来驱动腺泡化生。评估将评估Cox-2对Cox-2抑制Cox-2，或抑制五氧基菲林的抑制细胞因子合成，对细胞因子表达，炎性细胞浸润以及腺泡变质症和胰腺癌的发展的影响。还将确定抑制COX-2或细胞因子合成对既定病变中炎症细胞浸润的影响，以评估这是否会防止进一步发展或转化该疾病。公共卫生相关性：拟议的研究很重要，因为胰腺癌是所有人类恶性肿瘤中最致命的研究之一，缺乏良好的动物模型严重阻碍了对其病因，预防和治疗的研究。由于慢性炎症，COX-2和人类胰腺癌之间的关联，因此提出的工作很可能会产生有关胰腺癌发育中关键决定因素的信号通路和受体的信息，这应该有助于指导未来的化学预防和治疗研究。